This invention is generally in the field of methods and devices for the delivery of drugs, the delivery or measurement of electrical signals, or a combination thereof, in the treatment and control of cardiac diseases or disorders.
The application of electrical energy to myocardial tissue has been an important mode of therapy to treat several cardiac conditions. For example, in the presence of bradycardia, implanted cardiac pacemakers are routinely used to sense slow heart rates and deliver properly timed pulses of electricity of specified pulse amplitude and pulse duration to control the sequence (in the case of dual chambered pacemakers) and the rate of the heart beat. Another example is in the response to unexpected ventricular tachy-arrhythmias such as ventricular tachycardia and ventricular fibrillation, for which the implantation of cardioverters is indicated. These devices deliver a pulse of electrical energy to cardiovert, or defibrillate, the heart (i.e., to cause the heart to revert to normal beating) when a clinically significant ventricular arrhythmia is detected. Implanted defibrillators have also been used to treat patients with atrial fibrillation.
In addition, monitoring of the electrical activity of the heart has been done for many applications. For example, the 12-lead surface ECG looks at the resting state of the heart, as well as the ECG response to stress conditions. These methods may be used for indications of coronary heart disease. Ambulatory monitoring of the surface ECG has been used for monitoring patients for abnormal arrhythmias, as well as for monitoring the ST segment for occurrences of silent ischemia as a possible predictor for myocardial infarction (MI). Other applications have also included monitoring patients with transplanted hearts for transplant rejection. One feature of external ECG monitoring devices is the inclusion of heart rate variability monitoring as a predictive variable for sudden cardiac death or heart transplantation rejection. Within the field of implantable devices, heart monitoring for abnormal arrhythmias, episodes of syncopy, and heart failure have been documented. Implantable pacemakers and defibrillators also have increased their monitoring capabilities.
U.S. Patent Application No. 2002/0107553 A1 discloses an apparatus for treating ventricular dysfunction, heart failure, or imbalance of autonomic tone or endocrinological system, comprising at least one electrode located in a region associated with cardiac tissue in a patient's body; and means for applying electrical stimulation via the at least one electrode to improve the cardiac efficiency of the patient's heart. The apparatus can further include a drug delivery pump coupled to a drug delivery catheter that may be used with cardiac stimulation to provide a biologically-active agent to tissue to prevent anticipated or detected physiological insults. It would be desirable to provide improved and/or alternative therapeutic devices and methods useful in treating or managing cardiac diseases and disorders, including arrhythmias. It would be desirable to provide implantable devices providing enhanced control of drug delivery in an apparatus for the delivery or monitoring of electrical signals to and from tissues in cardiac applications.
Congestive heart failure (CHF) is a chronic condition in which the heart does not pump sufficient blood to meet the body's needs. Typical symptoms are relatively non-specific, but include shortness of breath (dyspnea), fatigue, peripheral limb swelling (edema), fluid in the lungs (pulmonary congestion), weight gain, and abnormal lung sounds (rales). The underlying causes of these symptoms are fluid overload, vasoconstriction, and reduced myocardial contractility. Frequently, the patient's dyspnea becomes more severe than usual, resulting in admission to an emergency room for relief. Traditional intervention has involved the administration of diuretics, vasodilators, and drugs that improve contractility (inotropic agents). Such therapy is palliative; 50% of admitted patients are readmitted with similar symptoms within six months. In 2001, an estimated 1M patients were admitted to U.S. hospitals for CHF; it is the single largest expense for Medicare, at greater than $38B annually.
Within the past 15 years, three specific hormones have been identified which are expressed in response to CHF. Atrial natriuretic peptide (ANP) is expressed by cells in the cardiac atria during atrial distension. B-type (or brain) natriuretic peptide (BNP) is expressed by cells in the ventricular myocardium during overload or stretch. C-type natriuretic peptide (CNP) is released by cells in the endothelium in response to shear stress. When these hormones are released, they produce vasodilation, excretion of sodium, reduction in aldosterone levels, inhibition of the renin-angiotension aldosterone system, and inhibition of sympathetic nervous activity. All of these effects are beneficial to the CHF patient. It has also been reported that natriuretic peptides can modulate the remodeling of the heart muscle, which is a typical occurrence in CHF patients in response to the increased pumping demand (Naohisa, et al., “Cardiac fibrosis in mice lacking brain natriuretic peptide,” PNAS 97(8):4239-44 (2000)). In addition, a rapid, bedside assay for BNP is available to facilitate diagnosis of CHF and its severity, and has been demonstrated to predict future CHF-related cardiac events. Unfortunately, in patients with severe CHF, the positive effects of these hormones, in the quantities that they are naturally expressed, are insufficient to relieve the symptoms. As a palliative strategy, a recombinant form of human BNP has been developed (Natracor-Scios, Inc.) and is becoming a common in-hospital intervention for progressive CHF, including acute episodes of severe dyspnea. Typical in-hospital intravenous (IV) administration includes a loading bolus of 2 μg/kg (˜140 μg), followed by infusion of 0.01 μg/kg/min for 24 hrs (˜1000 μg) or for 48 hours (˜2000 μg). Blood pressure is routinely monitored due to the potential for hypotension.
It is desirable to intervene in CHF as early as possible, in order to preempt, or at least delay onset of, acute episodes of dyspnea. In many cases, administration of one or more drugs is a central part of the intervention. However, the administration of drugs in such circumstances may be problematic, in that the one or more drugs need to be administered over an extended period of time, to maintain the desired bioavailability of drug over time. A key limitation is patient compliance, particularly in the absence of acute symptoms, in that patients are often unwilling to accept (painful) daily or even weekly injections as the drug delivery means for extended periods. Moreover, for those drugs that can be (non-painfully) administered orally, the patients may forget to take them on schedule or at all. To deal with these strategies and limitations, a number of pharmaceutical companies have developed extended release formulations for numerous drugs, whether for oral or parenteral administration. These formulations typically rely, for example, on PEGylation or controlled release formulations, in an effort to avoid RES (reticuloendothelial system) uptake and control plasma drug levels for the purpose of extending the period between injections. Overall, this strategy has had mixed results, in part, because for many of the approaches, the strategy or technique employed for one drug is not readily transferable to another drug. It would therefore be desirable to provide a drug delivery system which avoids the need for frequent or continuous parenteral administration for use in the management or treatment of a variety of diseases, disorders, or conditions. It would also be desirable to reduce or obviate the need for a patient suffering from CHF to be admitted to a hospital for treatment of acute symptoms, preferably by providing a means for earlier drug intervention, particular in combination with a means for monitoring the patient's cardiovascular and other properties. Such an early intervention system would be highly desirable in the management of CHF or in other therapeutic or prophylactic applications.